α-Melanocyte-Stimulating Hormone Inhibits NF-κB Activation in Human Melanocytes and Melanoma Cells

α-Melanocyte-stimulating hormone is produced by several different cell types including neural cells, endothelial cells, monocytes, and keratinocytes. A biologic role in melanocyte pigmentation is widely recognized, but more recent studies describe a part in modulating inflammatory and immune responses. The aim of the this study was to investigate the mechanism by which α-melanocyte-stimulating hormone antagonizes proinflammatory cytokine action. We report that α-melanocyte-stimulating hormone (10–9 M) was effective in opposing a tumor necrosis factor-α stimulated increase in NF-κB DNA binding activity in: (i) normal ocular melanocytes; (ii) cells cultured from ocular melanoma tumors; and (iii) two cutaneous melanoma cell lines. NF-κB is activated by many inflammatory mediators and controls transcription of genes required for immune and inflammatory responses. The transcription factor complex was positively identified as the p50/p65 heterodimer, recognized to have transcriptional activating potential. Maximum reduction of NF-κB DNA binding activity with α-melanocyte-stimulating hormone was detected 2 h after cellular stimulation and varied from between 53% and 18% depending on cell type. Whereas the acute inhibitory effects could be mimicked by elevating cyclic adenosine monophosphate, α-melanocyte-stimulating hormone was not found to have any effect on the relative level of IκBα protein expression over 24 h. These data show that α-melanocyte-stimulating hormone has a pronounced effect on NF-κB activity in melanocytes and melanoma cells, identifying a specific dimeric complex, and suggest this to be a key pathway by which immunomodulation/anti-inflammation may operate. The results may also be considered in the broader context of general inflammatory pathologies concerning cells which express α-melanocyte-stimulating hormone receptors and utilize the NF-κB signaling pathway